Project Summary The gut microbiome, mucosal immune cells and HIV-1 virions influence each other's functions through intimate and multifaceted interactions that determine disease outcomes in infected individuals. In this multi-PI proposal, we will test the central hypothesis that HIV-1 infection causes a profound disruption of the mucosal immune system, which does not resolve following the initiation of combination antiretroviral therapy (cART). By interrupting key signals between the microbiota and the host's immune system, HIV-1 elicits profound intestinal immune alterations that cause dysbiosis. This latter triggers a self-perpetuating, maladaptive feedback loop that impairs the regulation of viral quasispecies, promotes intestinal persistence of HIV-1 virions and, in a subset of patients, causes suboptimal immunological reconstitution following initiation of cART. The aims of this research program will be achieved through a unique collaborative effort involving three highly complementary groups. Dr. Saurabh Mehandru, PI, is a trained gastroenterologist with more than 15 years of experience in the field of HIV-1 infection and several key contributions on its impact in mucosal immunity. He will recruit infected subjects, obtain gut tissue, and profile intestinal and systemic immune populations along with HIV-1 reservoirs in the gut (Aim 1). Dr. Andrea Cerutti, Co-PI, is a world-renowned expert in the biology of mucosal B cells from both healthy and HIV-1-infected individuals. He will study intestinal IgA responses in the HIV-1-infected gut mucosa, focusing on the B cell ontogeny, clonotypic architecture and bacterial reactivity of IgA1 and IgA2 subclasses. He will also define the impact of unbalanced IgA1 and IgA2 responses on microbial translocation, gut inflammation and HIV-1 replication (Aim 2). Dr. Jeremiah Faith, Co-PI, is an internationally recognized leader in microbiome research, with several seminal contributions to this field. He will characterize HIV-1-induced alterations of the gut microbiome and their impact on HIV-1-induced mucosal IgA perturbations. He will also use gnotobiotic mice harboring the gut microbiota from HIV-1-infected patients or healthy controls to test the impact of cART on intestinal commensal bacteria independently of the host disease status (Aim 3).